In 2005, 7.6 million people worldwide died of cancer. Based on projections, cancer deaths will continue to rise with an estimated 9 million people dying from cancer in 2015, and 11.4 million dying in 2030. Each year in the European Union (EU) countries, nearly two million people are diagnosed with cancer and there are over one million deaths from the disease (Cancer Research UK). It is estimated that there are nearly three million people alive in the EU who have received a diagnosis of cancer in the last five years (Cancer Research UK).
There are over 50 drugs used in cancer treatment, but many of these drugs have an average efficacy of about 20% and produce significant side effects. Cancer patients often forego treatment in order to avoid the decreased quality of life associated with side effects such as nausea, vomiting, loss of appetite, weight loss, generalized weakness, and hair loss. In fact, there is a significant demand for drugs that counteract the side-effects of anti-cancer therapy (e.g., Procrit®).
Snake venoms have demonstrated cytotoxic activity on tumour cell lines in vitro, although their anticancer properties in animal models have been studied only in a limited manner. The venoms from cobras contain large amount of basic, non-enzymatic peptides of molecular weight 6.8 kDa, generically called Cardiotoxin, which display cytolytic activity on a broad variety of tumor cells, and to a lesser extent, normal cells. Crotoxin, isolated from the venom of the South American rattlesnake, Crotalus durissus terrificus, has proven to have significant and broad acting anti-tumour activity both in-vitro and in-vivo. Its increased affinity for cancer cells is due primarily to the target subunit (A, crotapotin) and cell death is brought about by the B subunit (Crotactine) through the membrane-disrupting enzymatic activity. It has significant potential as a therapeutic agent, but it also has significant neurotoxic activity. Crotoxin, however, induces tolerance to its neurotoxic effects without altering the cytolytic properties, permitting the use of doses above that which would normally be lethal to the host. Mice injected daily with progressively increasing doses of Crotoxin develop tolerance to the lethal action of the toxin. Treated mice tolerated daily doses of Crotoxin 20 to 35 fold higher than the original LD50, without the characteristic signs of toxicity. It has a significantly higher lethal activity toward cancerous cells than normal cells, and this effect has been presumed to be due to the altered make-up of the cell membranes produced by rapidly proliferating cells. The sensitivity of cancer cells to Crotoxin has been associated with their expression of epidermal growth factor, a surface receptor associated with malignancy. Cancer cell lines with the highest sensitivity to Crotoxin include lung, CNS, and melanoma.
Crotoxin has been used in several human safety studies alone and in combination with Cardiotoxin (a combination of Crotoxin and Cardiotoxin in 1:1 ratio is known as VRCTC310) in patients with refractory cancer. Crotoxin, administered by intramuscular injection, was well tolerated when administered alone or in combination with Cardiotoxin, with a maximum tolerable dose (MTD) of 0.21 mg/m2. Upon intramuscular injection Crotoxin achieves maximal circulating levels at 1 hour and is effectively cleared within 24 hours. Several severely ill patients have been reported to respond to treatment with reduced tumor burden, amelioration of pain, and improved quality of life. Given intramuscularly, Crotoxin gives objective clinical responses in doses close to the maximum tolerated dose (MTD). Preclinical animal data suggests that, by using a dose escalation protocol, the administration of very high doses can be achieved without adverse toxicity because the host becomes tolerant to the neurotoxic effects.
To date, subjects treated with Crotoxin have an overall response rate of 43% in a variety of tumour types. When compared to current biologic therapies, Crotoxin appears to be almost twice as active as its nearest competitor. While many other biologic therapies must be combined with conventional treatments and only serve to extend survival by marginal amounts, Crotoxin is a monotherapy, and has demonstrated sufficient activity to results in complete remissions in a relatively high percentage of terminally ill subjects under protocols that have not yet been optimized. It appears that Crotoxin has its highest cytocidal activity against highly malignant cancers, yet the side-effect profile is quite mild in comparison to other forms of chemotherapy or radiotherapy. Side-effects (e.g., diplopia, strabismus, ptosis, peripheral blockade of neuromuscular transmission) do exist, however, and have been reported in dose tolerance studies (Cura, J. et al., “Phase I and Pharmacokinetics Study of Crotoxin (Cytotoxic PLA2, NSC-624244) in Patients with Advanced Cancer,” Clinical Cancer Research, Vol. 8, April 2002, p. 1033-1041).
What would be of great benefit, would be the development of methods for optimizing higher dosage levels of Crotoxin while minimizing the neurotoxic side-effects.